Influenza, respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) continue to be major health burdens, each year causing millions of illnesses and tens of thousands of hospitalizations & deaths in the U.S. Although designed to reduce this burden, influenza vaccine has variable effectiveness (VE) from year to year due to host factors, environment, and virus & vaccine characteristics. Data from the US Flu VE Network helps CDC to evaluate vaccine policy, WHO to select vaccine strains and clinicians to use antivirals. We propose a test-negative case-control (TNCC) study to determine influenza VE in UPMC, which serves diverse populations in 500 clinical sites. UPMC wins awards as one of the most wired health systems in the U.S. UPMC preferentially uses high-dose vaccine for persons >65 years, routinely records vaccination status in its electronic medical record and has a two-way interface with the state immunization registry. Our proposal has a strong foundation of current participation in the US Flu VE Network with a multidisciplinary research team with the highest follow-up survey completion rate and enrollment numbers exceeding requirements. Our award-winning, high-throughput lab proposes analyses of influenza, RSV and HMPV. Each virus season definition is supported by >14,000 clinical multiplex respiratory virus tests and ongoing syndromic surveillance. We add agent-based modeling at the Pittsburgh Supercomputer Center. We are a CDC inpatient VE network site, thus we can compare VE for outpatients and inpatients. Specific aims include: 1) Using TNCC methods, determine annual influenza and RSV (after licensure) VE against laboratory-confirmed, medically-attended, acute respiratory infections among outpatients in 3 age groups: 6 mos.-18 yrs., 19-49 yrs., and >50 yrs.; 2) Determine the annual, population-based burden of influenza, RSV and hMPV in the same age groups, using the participating primary care sites as the source population, conduct sensitivity analyses and agent-based modeling on the impact of vaccination options; 3) Prepare for studies related to an influenza pandemic, describing the epidemiology, effectiveness of antivirals and/or pandemic vaccines, including pilot studies on patient portal/phone enrollment.